In multicellular organisms, about 5% of the genome is devoted to proteins acting in the defense against infections (Lander, E. S. et al., Nature 409, 860-921, 2001; Waterston, R. H. et al., Nature 420, 520-562, 2002, each of which is incorporated by reference in its entirety). Loss or dysfunction of certain defense genes results in increased vulnerability to infection as exemplified by over 80 known primary human immunodeficiencies (Waterston, R. H. et al., Nature 420, 520-562, 2002, incorporated by reference in its entirety). Immune cells respond to the presence of microbes with an increased capacity to destroy the invading pathogen concomitant with the production of a variety of potent cytokines and other inflammatory mediators. The produced inflammatory molecules have the capacity to activate many more immune cells and other effector cells distant to the focus of the infectious site, which can lead to a coordinated immune response to the infectious agents.
Toll-like receptor (TLRs) TLRs are transmembrane signaling receptors that can directly bind to a wide spectrum of microbial structures that include lipids. After ligand binding, signaling pathways can be activated leading to transcription of genes involved in the defense against the invading microbes. The importance of TLRs in the detection of microbial pathogens and their role in the induction of mechanisms intended to clear the infection is now well-documented (Hemmi, H. et al., Nature 408, 740-745, 2000; Takeuchi, O., Hoshino, K. & Akira, S., J Immunol 165, 5392-5396, 2000; Takeuchi, O. et al., Immunity 11, 443-451, 1999, each of which is incorporated by reference in its entirety). Certain members of the TLR family are also involved in the recognition of self-epitopes that appear in non-infectious alterations of the normal physiological state.